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Vernette J. Molloy, MBA, RN, is vice president of GCPA, Inc., Fairfax Station, Virginia.

A new reference guide clarifies uncertainty surrounding this sometimes misunderstood document.

A Closer Look at 1572: Interpreting the FDA's Statement of Investigator Form

A Closer Look at the 1572: Interpreting the FDA's Statement of Investigator Form

Alzheimer’s disease (AD), as well as other neurodegenerative dementias, such as frontotemporal dementia (FTD), can be characterized by progressively worsening deficits in several cognitive domains, including language. Patients with these conditions may demonstrate different speech patterns, such as difficulty in retrieving words (anomia), reduced information content, sentence comprehension deficits, and a lack of cohesion in discourse. Despite the prevalence of language characteristics as a symptom of these disorders, tools used to identify the extent of cognitive impairment in the study of AD and FTD do not typically monitor speech or rely on subjective ratings. Growing awareness of the opportunities that language evaluation can bring to clinical research is driving interest in speech-based digital biomarkers to evaluate changes in cognition and achieve more sensitive detection of the impact of treatments.

Challenges of detecting change in AD and FTD trials

Investigational drugs for AD and FTD have an extensive history of failing to demonstrate efficacy in Phase II and Phase III clinical trials. In trying to find reasons for these setbacks there is agreement that the limited sensitivity of current clinical trial endpoints may be a factor. Most of the standard primary endpoints used in AD and FTD research are clinical measures of cognition and/or function, such as the Clinical Dementia Rating (CDR) scale. While global rating scales serve a helpful purpose in providing a quantifiable clinical judgement about disease severity, there is an awareness that these tests do not adequately capture slight changes or improvements in a patient’s condition.

Putting questions on sensitivity aside, these standard approaches to testing are also hugely complex, difficult to administer and time intensive. A single test can take up to an hour to complete. Most also need to be administered by a clinician or psychometrist, meaning that patients are unable to complete them remotely. Repeatability may also pose challenges due to the potential for non-memory impaired patients to learn what to expect if these same tests are revisited regularly.

With the pressing need to develop and evaluate disease-modifying treatments for these diseases, there is an appetite from researchers for new tools and more sensitive means of measuring function and cognition in AD and FTD patients. Language represents a huge opportunity. As more sophisticated, automated, and objective ways of analyzing speech come into the frame, there is potential to gain insight into the language function of patients in a way that has historically not been achievable.

The adoption of speech as a biomarker in clinical research has the potential to capture more subtle speech and language changes in patients with cognitive impairment. People with AD and FTD may struggle to recall words, they may resort to basic vocabulary, construct simpler sentences, and speak at a slower rate. While clinicians and investigators may notice subtle language problems in patients at the early stages of these diseases, they do not currently have the tools to objectively characterize these changes and how they worsen or improve over time.

Technology that can facilitate the automated assessment of speech can provide more objective measures to complement clinical rating scales. Winterlight’s approach involves automatically extracting hundreds of acoustic and linguistic properties of natural speech. The fine-grained data can be used to characterize the speech patterns associated with AD, FTD, and other neurodegenerative disorders. The platform uses short-recorded speech samples captured through speech tasks including picture description, paragraph reading, paragraph recall, phonemic fluency, semantic fluency, and object naming.

These advancements are helping to build a more complete picture of the common aspects of speech and language that decline with the progression of certain dementias. In analyzing just one to five minutes of a patient’s speech, hundreds of linguistic cues can be identified that may offer more accurate insight into the severity of their condition. These cues include lexical diversity, syntactic complexity, semantic content, and acoustics. Integrating speech-based technology into the design of AD and FTD clinical trials has the potential to contribute detailed insights into the subtle ways that patients’ symptoms improve or deteriorate as a study progresses.

From the patient’s perspective, testing via these types of platforms may also bring considerable improvements and reduce burden. As with all clinical trials, keeping AD and FTD patients, and their caregivers, engaged with a study is paramount. Typically, assessments are administered by study sites via tablets. A trained rater would walk the participant through a brief speech assessment, taking under five minutes to complete. The assessment would prompt them to speak in response to simple instructions; this may be a request to describe a picture, or simply asking a patient to express how they are feeling that day. The patient’s speech is recorded via the device’s microphone, with recordings uploaded to a cloud-based platform. The speech recordings are analyzed using Winterlight’s speech analysis platform and outcome measures are provided to the trial sponsor as an exploratory endpoint.

Assessments can also be made available to patients through their own tablets or smartphones, as well as devices provisioned by sponsors, for remote collection. Removing the need for patients to visit a site for this type of testing makes it easier for insights to be collected more frequently than may have been possible using traditional methods. Winterlight’s technology is currently being used in several Phase II and III clinical trials for AD and FTD, with many patients reporting that the assessments are easy-to-use and less taxing than other clinical assessments they have experienced. This work is helping to build greater understanding of the speech changes that occur in these patients over time.

The future of speech assessment in clinical trials

There is tremendous potential for neurological language assessments to improve the way that clinical trials are run, and the impact of new treatments measured. As command of speech and language are ecologically and functionally relevant clinical markers of disease progression, objective tools can help generate novel, sensitive endpoints able to be administered remotely and at lower burden to the patient. While speech-based biomarkers are currently being used as exploratory endpoints, there is increased awareness of the enhancements they may bring to the accurate and sensitive measurement of cognitive health in AD and FTD research. As more evidence-based data and validation is gained, it is anticipated that these measures will eventually be adopted as primary and secondary endpoints and may provide more detailed insight into the subtle ways that new treatments are impacting cognitive health.

 is the Director of Clinical Research at 

Future shows great potential for neurological language assessments in clinical trials.

How Speech-Based Digital Biomarkers are Redefining the Measurement of Disease Progression in Neurodegenerative Dementia Trials

AiCure, an AI and advanced data analytics provider, is working with the Defense Health Agency’s (DHA) PTSD Drug Treatment (PTSD-DT) program to deploy its medication adherence platform to guide patients in their compliance to complex treatment regimens, as well as its digital biomarker solution to capture the subtleties of a patient’s response. As PTSD has a wide range of symptoms, 

 aims to develop a precision medicine approach to prescribing the most effective therapy based on a patient’s unique biological and clinical characteristics. Rich Christie, MD, PhD, Chief Medical Officer at AiCure, spoke to our sister publication 

 Can you provide the background on AiCure’s digital biomarker solution as a whole?

: During a clinical trial, a precise and accurate understanding of a patient’s response to treatment is critical to measure the state of their disease and a drug’s impact. Traditional means of measuring a patient’s well-being, including sporadic in-person assessments or a patient’s self-reported outcomes, only tell clinicians how a patient is feeling at that moment in time. The stretches between these check-ins can tell an entirely different story, filled with critical, subtle cues about their condition.

AiCure’s AI-powered digital biomarker solution enables remote detection of subtle changes in a patient’s health status and response to treatment by capturing audio and visual data between clinic visits. Accessed through AiCure’s Patient Connect application, patients use their smartphone’s front-facing camera to complete brief assessments. AiCure’s algorithm then analyzes behavior, such as emotional expressivity, physical movement and speech patterns. By frequently aggregating these sensitive, objective insights, AiCure empowers pharmaceutical companies to improve their understanding of the disease and treatment side effects, elevating the integrity of their trial data, and optimizing patient outcomes.

 How does the technology work in the context of the DHA partnership?

 The DHA PTSD Drug Treatment Program is conducting an adaptive platform trial designed for the efficient and cost-effective testing of multiple PTSD treatments in both active service members and veterans. AiCure's medication adherence platform guides patients in their compliance to complex treatment regimens. The biomarker solution is described above, and the application features integrated built-in reminders and a communication system, allowing sites to contact the participant if they’ve missed a dose or check-in.

: Can you describe the challenges of PTSD treatment?

 PTSD has a wide range of symptoms and has significant variation in how it presents across patients. Eighty percent of PTSD patients have at least one additional comorbidity such as depression, anxiety or substance abuse disorder, further complicating diagnosis and treatment. Despite the societal, financial, and emotional strain that PTSD exerts upon patients, there are only two FDA-approved therapies on the market.

The PTSD-DT Program's adaptive platform trial will evaluate the effect of therapeutics on a patient's PTSD symptoms over 12 weeks. Because medication compliance has historically been a significant methodological problem in PTSD clinical trials, AiCure's adherence platform will offer patients the necessary support to ensure correct dosing. The digital biomarker solution can be used to capture the subtle changes we discussed earlier, and may help investigators identify the right drug for the right patient, or allow clinicians to intervene in a patient's treatment plan in a timely manner if the drug is not likely to be effective.

 What does it involve in terms of patient interactions?

 Each time a patient doses in the trial, they will use the AiCure application. The smartphone-based application leverages computer vision and AI to remotely assess patient dosing behavior, ensuring the right patient ingested the right drug at the right time. This allows sites to monitor adherence and follow up with participants in instances of non-adherence. For the biomarker assessments, participants will be asked to perform simple tasks, such as describing images presented through the AiCure app in a few sentences to the camera of the smartphone, in order to record and analyze their responses.

 How many patients will participate in the PTSD clinical trial?

Rich Christie, MD, PhD, Chief Medical Officer at AiCure discusses the use of the company's technology in a clinical trial for PTSD.


PTSD Study Uses Precision Medicine Tech from AiCure

The FDA and other regulatory bodies have issued multiple guidance documents addressing technology tools that are used in clinical trials. FDA guidance documents include Computerized Systems;

 is also available online. In 2010, the European Medicines Agency (EMA) issued a Reflection Paper on electronic source records in clinical trials,

 and recently, the Medicines and Healthcare Products Regulatory Agency (MHRA)

 issued a document on data integrity. In 2016, the Chinese FDA issued Technical Guidelines on Electronic Data Capture for Clinical Trials.

 issued a document addressing the use of CDISC standards to facilitate the use of electronic source data in clinical trials.
	
	The regulatory push to the paperless clinical trial has occurred despite a pharmaceutical industry that has been risk-averse in adopting modern-day technology tools that could support clinical trials. This risk aversion is in part due to fear by sites and sponsors of receiving a FDA Form 483.

 What if the FDA turns down an application if it discovers that, for example, a patient was born in 1982, when in the study database it is recorded as 1983, even when there is no impact on the study results? The clinical sites are also fearful of losing business as a result of any FDA Form 483 finding, however minor.
	
	The major stakeholders in the clinical trial enterprise include study subjects/patients, sponsors, clinical researchers, regulators and the public at large. Now that the electronic world has entered the clinical trials space, as part of routine pre-approval inspections there will be an assessment of the impact of electronic systems on 1) informed consent; 2) data integrity and accountability; 3) protocol compliance; 4) monitoring of the study by the sponsor, including risk-based monitoring; 5) patient safety by assuring that all safety events are accurately collected and reported, and 6) drug/device accountability.
	
	The following are examples of regulated clinical trial software currently being used:

		Electronic patient reported outcomes (ePRO)

		Electronic clinical outcome assessments (eCOA)

		Dedicated tablets collecting and storing data in real time and transmitting data on a schedule to the study database

		Web-based systems collecting data in real time which transmit the data to the study database only after the source record is securely received and stored in an independent eSource storage location under control of the study site

		Mobile-based medical apps whose functionality could pose a risk to a patient’s safety if the app were to not function as intended


	
	It is strongly recommended that a risk-based approach to software validation be assessed for any medical software/app, even those not being used in clinical trials, as there are moral and ethical issues if any software used for medical decision-making does not act as intended.
	
	For software to be “reliable,” it needs to validated. Therefore, assuring that software is in a validated state is a key factor when regulators look at software products used in clinical trials. Fortunately, in 2002, FDA provided validation guidelines for software supporting regulated products.


	
	The following sections address some of the needed steps to assure that software used in clinical trials will be adequate to support regulatory scrutiny during pre-approval inspections and the review of marketing applications.
	
	


	
	Here are some critical questions to be asked concerning the “intended use” of the software, and depending on the answers, appropriate steps must be put in place.
	
	1. Why am I using the software?
	2. How is it being used?
	3. Will the data be used to support decision-making such as:

	4. Will the data be used to support primary and secondary outcomes?
	5. Will the data be used to support subject’s safety?
	6. How will patient privacy and confidentiality be maintained?
	
	


	
	A software product used in clinical trials must be validated and compliant with the Code of Federal Regulations (CFR) incorporated in Title 21 (Food and Drugs), Chapter I, Subchapter A, Part 11.

 21CFR Part 11, as it is commonly referred to, sets forth the criteria under which the FDA considers electronic records, electronic signatures, and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper.
	
	There is a distinction between validation and compliance. Validation is objective evidence which demonstrates that a given piece of software performs as intended against the user needs and the documented specifications and requirements.

	While it is true that software requirements and resulting features within the software can support compliance with 21 CFR Part 11, it is also true that no software or hardware system can be 21 CFR Part 11 compliant on its own. The software implementation, including processes and procedures for use of the system, are what constitute 21 CFR Part 11 compliance.
	
	And validation of the software goes beyond just the software requirements and resulting features necessary for Part 11 compliance. Validation is necessary for the entire software application and should be a defined part of the Software Life Cycle (SLC).
	
	


	
	There should be very clear SLC management documentation that contains the software development process from cradle to grave. In fact, many SLCs can go beyond the development process, to include ongoing support and even consideration for end-of-life for the software.
	
	In terms of popular development methodology choices, there is the Agile development methodology versus the traditional Waterfall approach. For the former, when it is very clear what the deliverable will be, one makes a detailed plan and then implements the plan. In contrast, the Agile approach accepts that there will be changes during software development and has built in flexibility to change direction at a moment’s notice.
	
	The first validation element is the software concept/requirements, or in other words, what is the problem we are trying to solve and why do we need this software? Usually an executive or the person driving the software writes the concept document to convey the mission and rationale of this new endeavor. Next, the “requirements” phase must clearly document what the software intends to do. For example, the software should allow for study subjects to enter study outcome data over the web using any device and any browser.
	
	Once the requirements are buttoned down, there needs to be clarity on how the requirements will be executed, which comes under the heading of “functional specifications.” For example, if the requirement is that “changes to the data base need to tracked,” then the functional specification could say that there needs to be an audit trail which must display the original value, the new value, why the change was made, who made the change, and what was the reason for the change.
	
	The next phase is left to the programmers and architects who create the very technical “design document.” This document basically is in “geek-speak” and we leave that document to the specialists. Once programming begins, the programmers work closely with the “testers” to test and debug the program until at some point the development team says the software is ready for a formal user acceptance test (UAT). In an Agile methodology, the design document, test plan and test scripts are written concurrently with development, iterating as features are refined. In a Waterfall methodology, the test plan and test scripts are often written with the design document, all of which is completed before development even begins.
	
	Once the “test plan and test scripts” are written and signed off, formal testing can usually begin right away. During testing, the testers document the “errors, bugs and fixes,” and when all that is completed, the software is “released” and signed off by those responsible and accountable. Post-release, “version control and change management” kick in. A plan is also put in place for the retirement of the software when it will no longer be supported or commercially available.
	
	


	
	A quality by design (QbD) methodology, which includes a risk assessment and risk mitigation strategies, is a critical exercise when building software. Using a Boeing 787 analogy, a plane has several electrical systems that control the engine and the coffee machine. We should not assign the same risk to the coffee machine not delivering hot coffee as we do to the engine failing on takeoff. Therefore, in a clinical trial, we propose the following for each risk:

		Assign a value of the risk to the study participant if a software failure happens

		Assign a value of the risk to the study itself if a software failure happens

		Assign a severity score if a software failure happens

		Assign a likelihood of detecting the software failure

		Then create a score and a risk-mitigation strategy for each risk


	
	A well-designed and well-written protocol can be viewed as one approach to an ideal quality manual. Therefore, in addition to standard protocol elements that we are all familiar with, the protocol should identify where and when electronic systems will be used, and then explicitly describe at a minimum, 1) all electronic systems being used; 2) the reason for their use; 3) how the systems will be used; 4) how the software will be controlled; 5) the basic elements of the risk assessment and risk mitigation strategies and; 6) data ownership and access controls.

	The inspectors will not usually do an assessment of the protocol design, as that was already done by the clinical team at the regulatory agencies. What the inspectors will do is attempt to determine whether 1) the protocol was followed; 2) there are SOPs supporting the protocol; 3) the site and sponsor followed what was stated in the protocol and SOPs; 4) the electronic case report form (eCRF) was intelligently designed to support protocol compliance; 5) there were system-generated management reports of site communications and protocol deviations/violations; 6) there was an integrated risk management plan and risk mitigation strategy; 7) there was a substantiated and complete root cause analysis of observed issues/events; and 8) there were follow-up corrective and preventative action plans (CAPAs) and that the follow-up actions were resolved as planned.
	
	From the safety perspective, the inspectors will want assurances that there was accurate reporting of safety events by evaluating 1) how safety data were collected; 2) the process for determining the source of original safety data based on a data source agreements; 3) a sample of source data from disparate sources, including review of source records written on pieces of paper, if relevant, and; 4) subject records maintained at the study site.
	
	

Are electronic source data reliable and fit for purpose?


	
	We are asked many times by those committed to paper records-sponsors or regulators-that if the system is fully electronic, how do we know that the data are real if there are no source records with which to compare the electronic record? Ironically, you can ask the same question about paper records; unless there are major controls of paper, notebooks, etc., nothing prevents a piece of paper from being destroyed and replaced by a new one. Bottom line, as some suspicious data trends are impossible to spot through manual review of records, fraud and dishonesty can usually only be identified through adaptable, validated checks and the use of informatics and multidisciplinary expertise. Clearly then, misconduct is not dependent of the collection medium of the original record (paper vs. electronic). Consequently, in a double-blind, randomized trial, one effect of fraud, if it occurs, could affect the study results by demonstrating that a potentially effective drug is ineffective from a statistical perspective (Type 2 error). This is where study monitoring techniques and fraud detection programs become vital.
	
	Therefore, when using off-the-shelf or proprietary software systems, the following are some of the quality questions that should be considered:

		Can the software provide any assurances that the study subjects are real?

		Are there validated systems to assure user authentication and control?

		Did the sponsor perform installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ)?

		How was access to the original data controlled?

		Were there date and time stamps for all transactions?

		Were there audit trails that can’t be overwritten?

		How was the data transferred to the study database?

		Can patient privacy and confidentiality be maintained?

Pre-approval inspections of an eSource program


	
	Based on our experience and the experience of others, when the regulators/inspectors arrive, they will need to review:

		Your organizational chart as it relates to the clinical trial

		Copies of relevant contracts/agreements

		Documents supporting vendor qualifications

		Documents supporting software validation/testing

		Corrective actions taken, reasons for actions taken, and the results of any actions

	As of this publication, two regulatory marketing applications have been submitted to FDA where direct data entry at the time of the office visit took place in lieu of maintaining paper source records. From the perspective of the pre-approval inspections at the clinical research sites, there were no Form FDA 483 findings related to study monitoring oversight and any of the electronic systems that were used for data collection. The inspections occurred at three of the five major medical centers that were inspected for the first application, and at five of the 20 outpatient clinical research sites that were inspected for the second application.
	
	The following are the redacted excerpts of the FDA inspection of the CRO (Target Health Inc.) for the first program that received marketing approval where the clinical research sites entered the majority of the data directly into the EDC system at the time of the clinic visit, and all documents were maintained in an electronic Trial Master File (eTMF; target document).
	
	

		This FY 2015 CDRH High-Priority Class II Device Application Inspection was conducted.

		This inspection was limited to the areas of compliance program 7348.810, “Sponsors, clinical research organizations and monitors.”

		Data line listings were provided with the background package, for comparison to the site eCRFs.

		An FDA 483 inspectional observation was not issued to management during this inspection.

 The clinical project manager develops a clinical data monitoring plan and safety monitoring plan for each study, using a company-specific template; these plans are approved by the sponsor before any site monitoring takes place.

a) The clinical data monitoring plan for the inspected study was reviewed and obtained.

 This study utilized direct entry of data, by the sites, into the EDC system using the eSource process (Target e*CTR; eClinical Trial Record).

a) This process allows for the original data to be stored in PDF format, in the repository, prior to being transmitted to the EDC database. The PDFs serve as original records.

The time is now for sites and sponsors to put away fears associated with data acquisition and monitoring technologies-and better support the regulatory push in recent years for standardized adoption of paperless trials.

Regulatory Considerations when Designing and Running 21st Century Paperless Clinical Trials

Conducting successful clinical trials in hematological malignancies requires an understanding of a rapidly evolving treatment paradigm that is increasingly nuanced, complex and patient-directed. Just as the underlying differences in biology and prevalence between blood cancers and solid tumors necessitates differences in treating patients, so, too, do they demand differences in clinical trial expertise and conduct. Sponsors developing hematological oncology therapies must capitalize on the principles and infrastructures shared by solid tumor oncology trials while adapting endpoints, study designs and considering patients' experiences to address the particular challenges related to investigating candidate treatments for blood-based cancers. This article examines the nuances of effectively and successfully conducting hematological oncology clinical trials.

	In the United States, someone is diagnosed with a blood cancer every four minutes and every 10 minutes; these malignancies result in a death.

 Despite this incidence, the three most common forms of blood-based cancers-leukemia, lymphoma and myeloma-comprised only an estimated 9% of all new cancers and 9% of all cancer deaths in 2013 in the United States.

 In comparison, the three most common US solid tumor cancers-breast, lung and colon cancer-together accounted for an estimated 34% of new cancer patients and 43% of cancer deaths in 2013.

  Globally, leukemia, multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL) and Hodgkin's lymphoma collectively accounted for only 6.5% of all cancer patients in 2012, excluding non-melanoma skin cancer.

	Despite a smaller incidence within the total oncology patient population, the global market for hematological cancer drugs reached an estimated $18.7 billion in 2012, with a projected target of at least $28.8 billion by 2017, equating to a compound annual growth rate of 9%.

	The growing hematological oncology therapy market will be fueled by the success of some of the more than 3,000 medicines in development for cancers.

 Driven in part by the application of new scientific knowledge and technologies to isolate and study the biology of malignant cells, a significant portion of hematological cancer medicines can truly be called novel. Of the 818 hematological oncology investigational projects underway, 627 had the potential to be first-in-class medicines, according to a January 2013 assessment.

	The ongoing research investment in understanding the fundamental biology of hematological malignancies will produce an enhanced and refined understanding of cancer pathologies in general as well as increasing the number of targeted therapies for blood cancers and enabling truly personalized treatments. Therefore, sponsors that ensure careful design and precise execution of their hematological oncology clinical trials will yield data that can inform, and perhaps significantly impact the greater oncology community.

	As an example, several years ago, Novella Clinical was approached by a biotech company to help rescue a pair of pivotal Phase III trials for its CXCR4 antagonist in development for hematopoietic stem cell transplantation. The sites participating in the trial had nearly shut down, refusing to submit any further patient data due to the supporting CRO overwhelming them with nonsensical queries. Simply put, the data and clinical management teams did not understand that, fundamentally, these patients are incredibly sick, and an “abnormal” lab value can be “normal” in this setting. For example, one would expect neutropenia or thrombocytopenia to occur following a transplant, and should not necessarily query lab data showing out of “normal” range white blood cell or platelet counts. 

	Novella was brought in to leverage its hematological oncology expertise in data management and biostatistics to rebuild the clinical database, clean up a substantial amount of the queries and help perform the analysis to support a new drug application (NDA). Ultimately, Novella turned the trial around and Mozobil® (plerixafor) for stem cell mobilization in NHL and MM patients was approved. 

	A hematological oncology trial is fundamentally different than a solid tumor study. Patient access alone is more difficult, as evidenced by the incidence rates above. Researchers should evaluate a hematological oncology study design relative to the feasibility of successfully enrolling and executing the trial and, if deficient, be able to offer modifications or alternative approaches that will lead to successful enrollment. To do so, they first need to understand the pathology, clinical manifestations and current treatment guidelines of the specific hematological cancer under study to fully comprehend all aspects of the most appropriate trial design. Sponsors and their partners must consider how these cancers influence the selection and precise use of terminology in defining important study parameters, of appropriate trial endpoints and of data management technologies as well as the selection and experience of patients.

. The correct clinical research use of terminology associated with hematological cancers requires familiarity and understanding. This defining process can present a notable learning curve for sponsors, trial staff or partners.

	For example, if a tumor forms in the lung, it is considered lung cancer, which has various subtypes, and if it spreads to other parts of the body, it is still called metastatic lung cancer. In contrast, bone marrow can be the starting location for several distinct cancers, many of which have their own subtypes and some of which can change and develop with time into a new cancer.

	Other classification systems define leukemia by the speed at which it develops, either chronic (slow) or acute (more quickly), as well as by the type of white blood cell affected, usually lymphoid or myeloid cells. Similarly, NHL is comprised of a large group of lymphocytic cancers divided into aggressive (fast-growing) and indolent (slow-growing) types that occur from either B-cells or T-cells. Classifying NHL is challenging not only because there are many subtypes, but also because of the methods used to determine the subtype. The World Health Organization (WHO) devised a system that not only uses cell morphology but also includes assessments of cell genetics and surface protein receptors.

	Recently, the most significant advance to clinical trial design, and an early glimmer into the potential of personalized medicine, is the need to identify patients with specific biomarkers before the patient can be considered eligible for study participation. Depending on the frequency of the marker used as entrance criteria, or even whether the marker is tested as standard of care at a given institution, the population of potential patients may be significantly reduced and necessitate a consequently large increase in screenings of patients. For example, adding the criteria that acute myeloid leukemia (AML) cancer patients be positive for a FLT3-internal tandem duplication (ITD) mutation reduces the patient population to just 25% of all de novo (first line) AML patients.

A sponsor must be knowledgeable of the bigger picture presented by the competitive hematological oncology treatment landscape, including current treatment guidelines and clinical practices. To appropriately drive development strategy in hematological oncology, a sponsor also must understand how to assess an investigational treatment's effect on the underlying disease, not just the patient's symptoms, so as to discern efficacy and safety comparative to current practices. Such evaluations will involve complex assessments using intricate endpoints that may involve counts of white blood cells, neutrophils, myeloblasts, myleocytes, as well as bone marrow measures, the spleen and the liver, among others.

	In addition, understanding the investigational therapy is critical. As more and more therapies have the potential to be first-in-class, such as antibody-drug conjugates or mutationally-selective inhibitors, potential clinical trial sites will likely have little to no experience with these new treatments. This knowledge gap can be addressed with appropriate site staff training before and during the trial. Study-specific training often is not just about the therapy but also the processing of complex and sensitive lab samples and the use and measurement of specific targeted endpoints, such as biomarkers.

The determination of endpoints differs significantly between solid tumor and hematological oncology. Most solid tumor cancer trials rely on the Response Evaluation Criteria in Solid Tumors (RECIST) to define a participant’s improvement/response, worsening/progression or stability. In contrast, the very nature of blood-based cancers requires that treatment trials rely on different measurements to determine treatment-related changes and disease progression, which can add more complexity to trial design, conduct and assessment.

	Overall survival (OS) remains the gold standard when evaluating cancer treatment effectiveness. However, progression-free survival (PFS) is the most commonly used surrogate endpoint for trials involving advanced cancers.

 Other progression-related OS surrogate endpoints include disease-free or event-free survival, response rate or objective response rate and time to progression.

	The smaller, single-arm design used in many hematological oncology trials usually precludes using time-to-event endpoints to reliably interpret treatment effects

 and determine OS. Therefore, these trials measure event-free survival, remission rates, duration of response as well as laboratory measures of biological activity. Major molecular response endpoints also are not uncommon in hematological oncology trials but require great specificity in determining what to measure and the techniques involved, based on the disease under study and whether it is acute or chronic. In the care setting of patients with chronic myeloid leukemia (CML), for example, a polymerase chain reaction (PCR) assay can evaluate molecular responses, namely measures of transcription levels of a specific fusion protein. Such molecular measures are now being adapted to the research setting. For example, entry criteria in CML trials using treatment-free remission as an endpoint require that patients achieve deep, molecular response levels.

	Hematological oncology trials also take advantage of technological developments to measure survival, particularly imaging, to provide greater specificity. For example, the 2011 biologics license application (BLA) submitted to the FDA for brentuximab vedotin was the first to use the agency's response criteria for lymphoma drugs, set forth in 2007,x which included FDG-PET (

F-fluorodeoxyglucose positron emission tomography) scans in the response assessments. The FDA considered PFS acceptable as an endpoint to confirm clinical benefit because an OS endpoint would not likely occur within a reasonable time frame. The BLA used data from two single-arm studies, both designed to show superiority using PFS as a primary endpoint and OS as a secondary endpoint. The FDA used these data to grant accelerated approval of the biologic for patients with Hodgkin’s lymphoma after failure of autologous stem cell transplantation (ASCT) or of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and for patients with relapsed systemic anaplastic large-cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

	As companies create a development strategy for a compound, the choice of endpoints is very important. Often, sponsors need to strike a balance between FDA-supported endpoints, cost, time and other endpoints, markers or measures that can quantify or qualify an efficacy signal but may not meet regulatory stringency. Designing trials accurately, understanding appropriate endpoints and measuring response using the correct technology are keys to trial success.

Whether in-house or through a partner, clinical research associates (CRAs) need to understand the significance and implications of blood count shifts as well as of transfusions and dosing timing. In the seriously ill patient populations of most hematological oncology trials, certain blood counts are expected to fluctuate because of their disease. For example, anemia in these patients can affect both drug activity and toxicities, so monitoring the anemia and its treatment in trials is important. When hemoglobin counts drop below a certain level, patients require a blood transfusion, which will raise the hemoglobin count. However, the hemoglobin count may also rise after a patient receives a treatment dose. An experienced CRA will know if such fluctuations are prompted by the transfusion, the dosage or the disease state.

Many biopharmaceutical and pharmaceutical companies are pursuing compounds that target hematological malignancies, and combined with an inherently rare patient pool, this naturally causes competition for investigator and institution participation, patient enrollment and key opinion leader relationships. Moreover, the world of hematological oncology specialists is even smaller than that of solid tumor specialists, making competition that much more intense. For a global trial, the rarity of some hematological oncology diseases can result in a lack of knowledgeable investigators or inconsistencies in standards of care from region to region. These variations can limit regional or country-specific options in site selection, which can have implications for trial conduct and regulatory clearance plans.

 found more than 70% of all responding practices reported offering a hematological oncology specialty for patients, only 26% of all practice types participated in clinical trials.x  A mere 11.3% of responding practices defined themselves as academic, with either teaching or research activities,

 making it clear that highly knowledgeable and experienced oncologists and hematologists practicing in community settings represent a significant source of referrals for clinical trials. However, at smaller community-based sites, a sponsor may need to offer more significant trial management support.

Sponsors of hematological oncology studies need to take several patient needs into consideration when recruiting, enrolling and retaining patients. The trial’s educational materials must not only clearly transmit information about potential treatment benefits and risks regarding their disease but also must include the potential impact study participation may have on one’s quality of life, such as the number of clinic visits, blood draws and radiographic studies as common in lymphoma.

	Additionally, trial teams must be aware that patients with hematologic cancers have disparate potential viewpoints that set them apart from solid tumor patients and that might impact enrollment and retention strategies. Some patients with lymphoma or leukemia, for example, have a chronic clinical course that extends for years, even decades. These patients are frequently interested in the potential a trial can offer, but want the confidence that an investigative therapy is likely effective and will not interfere with their lifestyle. They usually are less concerned about the pace of a trial and more concerned about invasive procedures, such as repeat biopsies or bone marrow exams, because of their risks.

	The opposite is true for patients with acute hematological cancers such as acute leukemia. Time is highly important to them, and they seek immediately available clinical trials and "instant" therapies they perceive as offering the potential for life extension, even if trials involve more invasive interventions, multiple clinical visits or radiographic studies. These patients find trials requiring long evaluations and limited chances to participate unappealing, but readily accept coming to the clinic frequently to confirm an investigative therapy is working.

	The better a hematological oncology trial can address the treatment agendas of individual patients, the more success the study will have in recruitment and completion.

	General patient rarity (most of these indications can be classified as orphan) combined with limited treatment specialists and centers, an intense competing trial landscape, and the potential for shifting standards of care both over time and across global regions makes proper site selection that much more critical to a study’s success right out of the gate. Disease terminology, classification and trial endpoints/response assessments are highly complex and can even morph over time, highlighting the need for an active knowledgebase in this space when designing the trial and when assigning the study team. Finally, the differences between the potential speed of progression within an indication (e.g., acute vs. chronic leukemia) and the resulting impact of invasive or frequent procedures on a patient’s willingness to participate in a given trial should be taken into account when designing the protocol. 

Conducting successful clinical trials in hematological malignancies requires an understanding of a rapidly evolving treatment paradigm that is increasingly nuanced, complex and patient-directed.

Vernette J. Molloy

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